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The evolutionary origins and catalytic importance of conserved electrostatic networks within TIM-barrel proteins

¹ Departments of Chemistry and ² Biological Sciences, California State Polytechnic University, Pomona, Pomona, California 91768, USA

(RECEIVED November 5, 2004; FINAL REVISION January 17, 2005; ACCEPTED January 18, 2005)

Conservation of function is the basic tenet of protein evolution. Conservation of key electrostatic properties is a frequently employed mechanism that leads to conserved function. In a previous report, we identified several conserved electrostatic properties in four protein families and one functionally diverse enzyme superfamily. In this report, we demonstrate the evolutionary and catalytic importance of electrostatic networks in three ubiquitous metabolic enzymes: triosephosphate isomerase, enolase, and transaldolase. Evolutionary importance is demonstrated using phylogenetic motifs (sequence fragments that parallel the overall familial phylogeny). Phylogenetic motifs frequently correspond to both catalytic residues and conserved interactions that fine-tune catalytic residue pKa values. Further, in the case of triosephosphate isomerase, quantitative differences in the catalytic Glu169 pKa values parallel subfamily differentiation. Finally, phylogenetic motifs are shown to structurally cluster around the active sites of eight different TIM-barrel families. Depending upon the mechanistic requisites of each reaction catalyzed, interruptions to the canonical fold may or may not be identified as phylogenetic motifs.

Keywords: protein family evolution; phylogenetic motifs; electrostatic networks; residue pKa; TIM-barrel proteins

Abbreviations: CuZnSOD, copper, zinc superoxide dismutase • PM, phylogenetic motif • COG, cluster of orthologous groups • TIM, triosephosphate isomerase • PSZ, phylogenetic similarity z-score • UHBD, University of Houston Brownian dynamics • PDB, Protein Data Bank • DHAP, dihydroxy-acetone phosphate • 2PG, 2-phosphoglycerate • TA, transaldolase • S7P, sedoheptulose-7-phosphate

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041221105.

Reprint requests to: Dennis R. Livesay, Department of Chemistry, California State Polytechnic University, Pomona, 3801 W. Temple Avenue, Pomona, CA 91768, USA; e-mail: drlivesay{at}csupomona.edu; fax: (909) 869-4344.

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